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Hypercoagulability is a prominent feature of coronavirus disease 2019 (COVID-19) and can lead to fatal consequences. Although the impact of COVID-19 on several disorders is well-established, its effect on congenital bleeding disorders (CBDs) is not well-documented. To address this ambiguity, a systematic review was conducted on the available studies to determine the impact of COVID-19 and vaccination aimed to prevent COVID-19 on patients with CBDs. We performed a systematic literature review using relevant keywords and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol. We conducted our search on the PubMed, Scopus, and Web of Science databases until July 2023. Out of 31 included studies, 12 case series covering 770 patients with CBD and COVID-19 were further analyzed. The majority of the patients had hemophilia A ( n  = 352, ∼46%) or hemophilia B ( n  = 74, ∼10%), while the remaining patients had von Willebrand disease ( n  = 43, 5.6%) or rare bleeding disorders (n = 27, 3.5%). A total of 25 deaths (3.2%) and 22 intensive care unit admissions (2.8%) were recorded. Bleeding complications were reported in the majority of the 12 case series ( n  = 7, 58.3%) and in most of the case reports ( n  = 8, ∼57%), while thrombotic complications were only reported in two studies (16.6%). The mortality rate ranged from 0% in five studies (41.6%) to 5.7% and the rate of hospitalization ranged from 0 to 40%. Bleeding complications were reported in a range of 0 to 81%, while the thrombotic complication rate in one study was 6.9%. The mortality rate varied from 0 to 5.7%, and the hospitalization rate ranged from 0 to 40%. Bleeding complications were reported in a range of 0 to 81%, while the rate of thrombotic complications in one study was 6.9%. Vaccination was reported in five case series, which included 821 patients with CBDs with the majority having hemophilia A ( n  = 479; 67.2%) and hemophilia B ( n  = 85; ∼12%). The most frequently reported side effects were myalgia (6.5%), flu-like symptoms (4.8%), fever (4.7%), and headache (4%). COVID-19 in patients with CBDs appears to provoke thrombotic complications and bleeding events more frequently, as well as a higher rate of hospitalization, which may be partially due to the increased risk of bleeding events. Although it seems that patients with CBD have lower mortality rates, further studies are necessary to fully understand this, especially considering comorbidities and low number of available studies., Competing Interests: None declared., (Thieme. All rights reserved.)

Competing Interests: None.

Coagulation factor (F) V is a glycoprotein that plays an essential role in the formation of the prothrombinase complex, which is critical for progressing clot formation. FV deficiency is a rare bleeding disorder with an estimated incidence of one per 1 million in the general population. The disorder is manifested with a wide array of clinical bleeding events. The most common bleeding features of FV deficiency are mucosal bleedings. Life-threatening manifestations are rarely seen in this disorder. FV deficiency is diagnosed using routine coagulation tests and FV activity assay. A wide spectrum of mutations including missense, nonsense, and frameshift is observed throughout the F5 gene. Although fresh frozen plasma is the dominant therapeutic choice, a newly introduced plasma-derived FV concentrate was found effective in in vitro correction of prothrombin time, activated partial thromboplastin time, and thrombin generation parameters in severe FV deficiency and should provide more targeted treatment for patients with FV deficiency in the future., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Congenital factor XIII (FXIII) deficiency is an extremely rare hemorrhagic disorder characterized by a deficiency of FXIII and associated with a high rate of morbidity and mortality. The disorder is more frequent in Iran, especially in Khash, a city in the southeast of the country. As identified in the current report, the prevalence of FXIII deficiency in this city is 1 homozygote per approximately 500 population (which is ∼4,000 times higher than the worldwide prevalence) with 3.5% heterozygotes. The disorder is accompanied by a high rate of mortality in rural areas of Khash, given an averaged observed rate of approximately three deaths per each family with FXIII deficiency, mostly due to late-diagnosis and/or misdiagnosis, and fetal consequences of both umbilical cord and central nervous system bleeding. Almost all patients with FXIII deficiency in the southeast Iran have a unique mutation in F13A gene (Trp187Arg), which leads to a severe FXIII deficiency. This mutation is used for pre-marriage and prenatal diagnosis, as well as for carrier detection and diagnostic confirmation. Fibrogammin P has been used worldwide for about one decade, along with different therapeutic regimens for prophylaxis treatment, major and minor surgeries, and successful delivery. Due to the rapid increase in the number of patients identified to have congenital FXIII deficiency, and the high rate of related morbidity and mortality, a comprehensive regional preventive program is necessary to prevent further expansion of this condition and decrease the burden on the health care system. The area of Khash city provides novel insights into severe FXIII deficiency due to its high prevalence in this region. This report also provides a review of FXIII deficiency, its diagnosis, prevalence, molecular basis, clinical manifestations, management, and treatment, with a particular focus on Iran, representing a hotspot for this disorder., Competing Interests: The authors state that they have no conflict of interest., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Intracranial hemorrhage (ICH) is a medical emergency. In congenital bleeding disorders, ICH is a devastating presentation accompanied with a high rate of morbidity and mortality. The prevalence of ICH is highly variable among congenital bleeding disorders, with the highest incidence observed in factor (F) XIII deficiency (FXIIID) (∼30%). This life-threatening presentation is less common in afibrinogenemia, FVIII, FIX, FVII, and FX deficiencies, and is rare in severe FV and FII deficiencies, type 3 von Willebrand disease and inherited platelet function disorders (IPFDs). In FXIIID, this diathesis most often occurs after trauma in children, whereas spontaneous ICH is more frequent in adults. About 15% of patients with FXIIID and ICH die; the bleeding causes 80% of deaths in this coagulopathy. Although in FXIIID, the bleed most commonly is intraparenchymal (> 90%), epidural, subdural, and subarachnoid hemorrhages also have been reported, albeit rarely. As this life-threatening bleeding causes neurological complications, early diagnosis can prevent further expansion of the hematoma and secondary damage. Neuroimaging plays a crucial role in the diagnosis of ICH, but signs and symptoms in patients with severe FXIIID should trigger replacement therapy even before establishment of the diagnosis. Although a high dose of FXIII concentrate can reduce the rate of morbidity and mortality of ICH in FXIIID, it may occasionally trigger inhibitor development, thus complicating ICH management and future prophylaxis. Nevertheless, replacement therapy is the mainstay of treatment for ICH in FXIIID. Neurosurgery is performed in patients with FXIIID and epidural hematoma and a hemorrhage diameter exceeding 2 cm or a volume of ICH is more than 30 cm 3 . Contact sports are not recommended in people with FXIIID as they can elicit ICH. However, a considerable number of safe sports and activities have been suggested to have more benefits than dangers for patients with congenital bleeding disorders, and are hence suitable for these patients., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Factor XIII deficiency (FXIIID) is a rare bleeding disorder with an estimated prevalence of 1 in 2-million population worldwide. In Iran, a Middle Eastern country with a high rate of consanguineous marriages, there are approximately 473 patients afflicted with FXIIID. An approximately 12-fold higher prevalence of FXIIID is estimated in Iran in comparison with overall worldwide frequency. In this study, we have undertaken a comprehensive review on different aspects of FXIIID in the Iranian population. The distribution of this disease in different regions of Iran reveals that Sistan and Baluchestan Province has not only the highest number of patients with FXIIID in Iran but the highest global incidence of this condition. Among Iranian patients, umbilical cord bleeding, hematoma, and prolonged wound bleeding are the most frequent clinical manifestations. There are several disease causing mutations in Iranian patients with FXIIID, with Trp187Arg being the most common mutation in FXIIID in Iran. Traditionally, the management of FXIIID in Iran was only based on administration of fresh frozen plasma or cryoprecipitate, until 2009 when FXIII concentrate became available for patient management. Various studies have evaluated the efficacy and safety of prophylactic regimens in different situations with valuable findings. Although the focus of this study is on Iran, it offers considerable insight into FXIIID, which can be applied more extensively to improve the management and quality of life in all affected patients., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)